JPS5989685A - Epoxy carbacephem compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [X is phthalimide or azide; Y is H or methyl; R is 1-5C lower alkyl (which may be substituted by a halogen), (substituted) silyl, benzyl or trityl, etc., provided that the phenyl nucleus thereof may be substituted by methyl, methoxyl or nitro]. EXAPLE:tert-Butyl (+ or -)-6,7-cis-7-azido-1-azabicyclo[4.2.0]octo-2,3-epoxy-8-oxo-2- carboxylate. USE:Useful as an intermediate for 3-hydroxy derivatives, etc. which are parent nuclei of cephalosporin analogs having antimicrobial action. PROCESS:A compound of formula II is reacted with a halogenating agent in a hydrous solvent, e.g. tetrahydrofuran (THF), at -10-+50 deg.C to give a compound of formula III (Z is halogen), which is then treated with a base, e.g. pyridine, in an inert solvent at 0-50 deg.C to afford the aimed compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (1) [wherein, A lower alkyl group (which may be substituted with ), a substituted silyl group, or a benzyl group, a benzhydryl group, or a trityl group (however, the phenyl nucleus of these groups is a methyl group, a methoxy group, or a nitro group). The epoxycarbacephem compound (hereinafter referred to as compound CI) represented by The same applies to compounds with other formula numbers).

No compound having an epoxy group is known not only for carbacephems but also for cephalosporins. Compound CI) is a useful intermediate that can be converted into a compound having antibacterial activity via a 3-hydroxycarbacephem compound, etc., which will be described later.

In the general formula CI), the "C□-C5 linear or branched lower alkyl group" for R is methyl, ethyl, propyl, t-/propyl, and phthyl.

i-butyl + 5ee-butyl + tert-butyl,
Examples include n-pentyl.

Examples of the group substituted with halogen for R include chloromethyl, 2,2.2-trichloroethyl, 2,2.2-trifluoroethyl, etc., and examples of the halogen include chlorine, fluorine, and bromine.

Examples of the substituted silyl include trimethylsilyl and 1-butyldimethylsilyl.

Compound CI) is represented by the general formula [■] CO,R (wherein, , synthesized according to Process I below.

(Process I) (In the formula, X, Y, and R have the same meanings as above, and 2 is a halogen atom) It can be carried out according to a temporary method of halohydrination of haolefin. Preferably, halohydrination is carried out by reacting compound [1) with a halogenating agent at -10 to 50°C in a water-containing solvent.

As a solvent, dimethoxyethane, tetrahydrofuran,
Dioxane, diethyl ether, acetone, dimethyl sulfoxide, dimethyl formamide, etc. can be used. As the halogenating agent, N-halosuccimide and N-haloacetamide are used.

tertiary butyl hypochloride, tertiary butyl hypochloride, halogen, etc. to compound [n] at 1 to 1.5
Use equivalent amount.

Epoxidation is carried out by converting the compound [■] with a base in an inert solvent from 0 to
This is done by processing at 50°C.

Inert solvents include dichloromethane, chloroform, dimethoxyethane, and tetrahydrofuran.

Dioxane, diethyl ether, toluene, benzene,
Ethyl acetate, dimethyl sulfoxide.

Use dimethylformamide etc. As a base, organic amines such as triethylamine, diethylamine, pyridine, 1,5-diazabicyclo[4,3,0:3nonene51118-diazabicyclo[:5.4.0:]]undecene are used for compound [l]. 1 to 2 equivalents are used.

Isolation of compound El) and compound CI) from the reaction mixture m
It can be carried out by techniques commonly used in the synthesis of penicillins and cephalosporins, such as extraction, chromatography, recrystallization, etc. Of course, the reaction can also be carried out without isolating the compound.

Compound (I) obtained according to the present invention can be obtained by the following process (1) developed by the present inventors (5) using, for example, zinc chloride, zinc bromide, aluminum chloride,
aluminum bromide, titanium tetrachloride, magnesium bromide,
Using lithium bromide, lithium iodide, lithium chloride, lithium perchlorate, hydrogen fluoride, tri-n-butylphosphine oxide, etc., 3-hydroxy compound (CIV), which is the core of cephalosporin/analogues with antibacterial activity, is produced. Furthermore, it can lead to the 3-methoxy form (IVI), and therefore, compound [T] is a useful intermediate. A detailed explanation of process (1) is illustrated by reference examples.

(Process ■) CI) [IV] [Y] For carbacephem compounds having a hydroxy group or methoxy group at the 3-position, see Chem, Pharm, Bull.

28(5) 1563 (1980).

(6) Among the compounds [■] obtained as above, C02
The ester group represented by R is penicillin.

Using methods frequently used in cephalosporin chemistry, substituents in the molecule, by selecting appropriate conditions and reagents,
It can be converted into a carboxyl group without damaging the functional group. Also X
If the substituent represented by
By a method of acting in the presence of a base such as pyridine, etc.
If the substituent represented by By introducing various acyl groups commonly used in the field of penicillin and cephalosporin chemistry into the amino group, cephalosporin analogs having useful antibacterial activity can be obtained.

Embodiments of the present invention are illustrated below.

Example 1. (g)-6,7-cis-2azido-1-azabicyclo[4,2,03oct-2,3-epoxy-
8-Oxo-2-carboxylic acid tert-butyl ester: (t)-6,7-cis-twoazido-1-azabicyclo[4,20]]octo-2.3-1 poxy-8-oxo-2-carboxylic acid, Method for producing 3-butyl ester. (to)
-cis-7-azido-1-azabicyclo[4,20]]
Octo-2-ene-8-oxo dicarboxylic acid, tertiary butyl ester 2v (7.58 mmol), 1,2-dimethoxyethane 2001, water 100ml! N-bromosuccinimide 2 was dissolved in a mixed solvent of
．． Add 02f (11.36 mmol) and continue stirring for 1.5 hours. Here is 10011 liters of ethyl acetate! After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off. Anhydrous methylene chloride 2 was added to the resulting residue.
Add 0-3 h and add 1.55 m of triethylamine to this.
and stir overnight at room temperature. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography using silica gel 802), n-hexane-ethyl acetate (4:
Both fractions containing the target product eluted in step 1) were collected and concentrated under reduced pressure to obtain 850 μm (40.1%) of a solidified product.

The physical properties of this product are as follows.

IR1,'KBr(>-ri: 3460,2980?
2120117801aX 74O NMR (CDCl, )δ: 4.89 (IH, d,
J=4.88Hz), 3.68(1)L br, s)
, 3.423.61 (IH+m), 1.68-2.
53 (4H, m), 1.51 (9H, 8) Example 2.
Production of (t)-6,7-cis-twoazido-1-azabicyclo[4,20]oct-2-hydroxy-3-bromo8-oxo-2-carboxylic acid, tert-butyl ester: (→-cis-7 -azido 1-azabicyclo[4,20
]] Octo-2-ene-8-oxo-2-carboxylic acid, tertiary butyl ester 21F (7.58 mmol) was added to 1.2
-Dissolved in a mixed solvent of 200 t of dimethoxyethane and 100 d of water, and while stirring under water cooling, 2.02 f of N-(9) bromosuccinimide (11,36 mm
ol) and continued stirring for 1.5 hours. Next, 100% of ethyl acetate is added, and the ethyl acetate layer is washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent is distilled off. The obtained residue was subjected to silica gel column chromatography, and the fractions containing the target compound eluted with silica gel 50v) and n-hexane-ethyl acetate (4:1) were collected and concentrated under reduced pressure to yield 1.7 or (az, zqb). ) to obtain an oily substance. This substance consists of two types of isomers. The physical properties of this product are as follows.

<Low polar isomer> 745 NMR (CDCl3) δ: 4.70 (IH* br,
s)t 4.70 (IH+d, J=4.88H2),
3.82-4.14 (2H, m) + 2.37-
2.62 (2Hl m), 1.69-1.93 (2H
,rn).

1.58 (9H, s) <Highly polar isomer> 745 lNMR (CDCl2) δ: 4.73 (IH, br,
8), 4.71 (IH, dlJ=4.89Hz), 3
．． 92-4.14 (2H, m), 1.742.53 (4
H+ m)+ 1.58 (9H9s) Reference example 1. (to)
-cis-7-azido-1-azabicyclo[4,2,0)
Octo-2-en/-3-hydroxy-8-oxo-2
-Carboxylic acid, tertiary butyl ester: Epoxy body ssoq(a,o
am mol) was dissolved in 20 g of anhydrous benzene, 2001 t9 of zinc chloride was added, and the mixture was stirred vigorously at 50° C. for 2 hours. The inorganic salts are separated in a furnace, and the F solution is concentrated under reduced pressure.

The obtained residue was subjected to silica gel column chromatography using silica gel 50f) and n-hexane-ethyl acetate (4:1).
Both fractions containing the target substance eluted are collected and concentrated under reduced pressure to obtain crystals of 1491v (17.5%).

The physical properties of this product are as follows.

IRl/)cHc13(crR-1): 29B0.
2120.1775.1660ax NMR (CD(J3)δ: 11.50(IH,8)I
4.85 (IH9d.

J=4.88Hz)+3.62 3.82(11(
+ m), 2.44-2.59 (2H1m)t 1.7
7-2.38 (2HI m) 11.55 (9H, 8) Reference example 2. (t)-cis-7-azido-1-azabicyclo(4,2,0)oct-2-ene-3-methoxy-8
-Oxo-2-carboxylic acid, tertiary butyl ester: Epoxy body obtained in Example 1 850cm (3.03mm
ol) to anhydrous benzene 2011L/! Add 200 μm of zinc chloride and stir vigorously at 50° C. for 2 hours. The inorganic salt was separated by furnace, an appropriate amount of diazomethane ether solution was added, and after stirring at room temperature for 30 minutes, it was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography.
Both fractions containing the target substance eluted with n-hexane-ethyl acetate (4:1) were collected and concentrated under reduced pressure to yield 100 μm (
11,2) crystals are obtained.

IR9CI (c'a@m-1): 2980.212
0.1775.1715aX NMR (cryct3) δ: 4.87 (IH, d,
J=4.89Hz)+3.76(3H,8), 3.
42-3.96 (IHI m), 2.40-2.72
(2) I, m), 1.79-2.33 (2H, m)
.

1.53 (9H+s) Reference example 3. (e)-cis-7-amino-1-azabicyclo[4,2,0)oct-2-ene-3-methoxy-8
-O; total 2-carbo/acid, tertiary butyl ester hydrochloride: methoxy compound obtained in Reference Example 2 19 s my (o,
a7m mol) was dissolved in 20d of ethanol, IN
HCI.

Add 0.673d and 50η of 10% palladium-carbon catalyst and perform indirect contact light for 30 minutes. The catalyst is separated and the p liquid is concentrated under reduced pressure. When 10al of ether is added to the obtained residue and the mixture is thoroughly crushed, the target product (13) 709 (34.1ch) is obtained as a solidified product.

IRl/)KBr(cm-”): 36703300
-30702730+ax 1770, 1715.1620 Reference example 4. (e)-cis-7-amino-1-azabicyclo[4,2,0)oct-2-ene-3-methoxy-8
-Oxo-2-carboxylic acid, trifluoroacetate: Amino compound 70y obtained in Reference Example 3 (0,2sm mo
1) in methylene chloride, 0.2 sit of trifluoroacetic acid was added under water cooling, and stirring was continued for 3 hours. After concentrating the reaction solution under reduced pressure, ether 5d was added and the mixture was thoroughly crushed to obtain 30 mg (40.2%) of the target product as a solidified product.

IRp”:”:rJc(cm-”): 3700-
3200.3100-2800゜+77oj 162
0+ 1550 side (■5OD) δ: 3.80 (3H
, s), 3.64, 4.02 (IH.

m) s 1.802.35 (2H+ m) (14) Procedural amendment January 27, 1980 Commissioner of the Japan Patent Office Sir 1, Indication of case 1982 Patent Application No. 200034 λ Name of invention Epoxycarbacephem compound 3. Relationship with the person making the amendment Patent applicant postal code 100 Address 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name
(102) Kyowa Hakko Kogyo Co., Ltd. (location: 03-201-
7211 extension 2751) Detailed explanation of the invention column 5 of the specification, contents of amendment (2) Add K "chloroethyl," after "ripronotyl," on page 3, lines 7-8.

(3) Correct "temporary" in line 11 directly below 4 to "general."

(4) Correct page 5, line 11 as follows.

"-5 and 1,8-diazabicyclo[5,4,0:]
(5) Directly below line 8, lines 15 to 12, [(±)-6,7-sisu production method. ” to be deleted.

(6) 1 Example 2 of 9 lines of 9. (±)-6,7-cis-twoazide-1-" is supplemented and corrected as follows.

[Example 2. (±)-6,7-cis-twoazido-1-
Azabicyclo[4,2,0]]octo-2,3-eboxy-8-oxo-2-carboxylic acid, tert-butyl ester: (1) (±)-6,7-cis-twoazido-1-'' (7
) Add the following sentence after line 3 on page 11.

r(2) (±)-6,7-cis-twoazido-1-azabicyclo(4,10)octo-2,3-eboki(2) Production of cy8-oxo-2-carboxylic acid, tertiary butyl ester : (±)-6,7-cis-twoazido-1-azabicyclo(4,2,0)oct-2-hydroxy-3-promo-8-oxo-2-carboxylic acid obtained in (1) above, 3 butyl ester 1.7F in anhydrous methylene chloride 20
- dissolves in

1.55-triethylamine was added to this mixture, and the mixture was stirred at room temperature overnight. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to obtain silica gel 80f),
Both fractions containing the target substance eluted with n-hexane-ethyl acetate (4:1) were collected and concentrated under reduced pressure to obtain 6801.
A solidified product of 51 (51,4N) was obtained. The physical properties of this product are exactly the same as those obtained in Example 1. ” (3)

Claims (1)

[Claims] General formula CI) [wherein, (optionally substituted with halogen), a substituted silyl group, or a benzyl, benzhydryl or trityl group (however, the phenyl nucleus of these groups may be substituted with a methyl, methoxy or nitro group) An epoxycarbacephem compound represented by